New aminomethylpiperidine compounds

ABSTRACT

The invention relates to compounds of general formula (I). ##STR1## in which X represents an atom of sulfur or oxygen, or a substituted or unsubstituted amino group; 
     R represents a hydrogen atom or any one of groups A, B, C, D, E, F, or G; 
     R&#39; represents a hydrogen atom, an alkyl group or any one of groups A, B, C, D, E or F, with R&#39;=H when R=G; 
     or R and R&#39; form, with the nitrogen atom to which they are attached, an optionally substituted piperazine ring. Medicaments.

The subject of the present invention is new compounds ofaminomethylpiperidine.

Numerous compounds of piperidine have been described in the literature.These include the compounds mentioned in Patent FR 2,618,435 whichpresent antihistamine properties or again in Patent FR 2,587,029 whichare useful in the treatment of allergies.

The compounds of the present invention differ from those described inthe prior art since the invention relates to compounds of4-(aminomethyl)piperidine substituted at position 1 by a heterocyclicgroup.

As well as being new, they possess very valuable pharmacologicalproperties.

They act both on the central nervous system and on the peripheralnervous system by means of the 5-HT_(1A) receptors for which they have avery great affinity. This property makes them useful in the treatment ofdepression, anxiety, stress, schizophrenia, pain, cardiovasculardisorders, and hypertension. They can equally be used to modify eatingand sexual behavior.

More specifically, the present invention relates to compounds of formula(I): ##STR2## in which:

X represents a sulfur atom, an oxygen atom, or an amino group optionallysubstituted by a linear or branched lower alkyl group,

R represents a hydrogen atom or any one of the following groups:##STR3## in which:

Z represents an oxygen atom or a CH₂ group,

Y represents a hydrogen atom,

Y' represents a hydrogen atom, or,

Y and Y' form together an oxygen atom,

R₁ represents a hydrogen atom, a halogen, a linear or branched loweralkyl group, or a linear or branched lower alkoxy group,

R'₁ represents a hydrogen atom, a halogen, or a linear or branched loweralkoxy group,

R₂ represents a hydrogen atom or a linear or branched lower alkyl group,and

m is equal to 0 or 1, ##STR4## in which

R₃ represents a hydrogen atom, a linear or branched lower alkyl group,or a halogen, ##STR5## in which:

R₄ and R'₄, the same or different, represent a hydrogen atom, a halogen,or a linear or branched lower alkoxy group, or form together, when theyare situated on two adjacent carbons, an ethylenedioxy group,

n is equal to 2 or 3, ##STR6## in which:

R₅ represents a hydrogen atom or a linear or branched alkoxy group (C₁-C₆), and

R' represents a hydrogen atom, a linear or branched lower alkyl group orany one of groups A, B, C, D, E or F, with the qualification that R'represents a hydrogen atom when R represents the group G,

R and R' form, with the nitrogen atom to which they are attached, apiperazine ring unsubstituted or substituted on the free nitrogen of thepiperazine by a phenyl group (unsubstituted or substituted by one ormore halogen atoms or alkyl (C₁ -C₆) or alkoxy (C₁ -C₆) groups);

the term lower indicates that the groups thus qualified have 1 to 6carbon atoms, and the dotted line in group B indicates the presence of asingle or double bond, their enantiomers, diastereoisomers and epimersas well as their addition salts with a pharmaceutically acceptable acid.

Among pharmaceutically acceptable acids can be mentioned, withoutimplied limitation, hydrochloric, sulfuric, tartaric, maleic, fumaric,oxalic, methanesulfonic and camphoric acids, etc.

The invention also extends to the process for preparing the compounds offormula (I), comprising the reaction of a compound of formula (II):##STR7## in which:

X has the same meaning as in formula (I) and X' is a halogen atom,

1/either with:

4-aminomethylpiperidine of formula (III): ##STR8## to lead to a compoundof formula (I/a), a particular case of compounds of formula (I):##STR9## in which X has the same meaning as in formula (I), which iscondensed on a compound of formula (IV):

    R--L                                                       (IV)

in which

R₁ represents any one of groups A, B, C, D, E or f,

L is a labile group such as toluenesulfonate, methanesulfonate or ahalogen atom,

the isomers of which have been optionally prepared by a conventionalpreparation technique,

to lead to a compound of formula (I/b), a particular case of compoundsof formula (I) ##STR10## in which X and R₁ have the same meaning asabove, the isomers of which are optionally separated by a conventionalseparation technique, which is submitted, if desired,

either to the action of a compound of formula (V):

    R"--L                                                      (V)

in which L has the same meaning as above, and R" is any one of groups A,B, C, D, E or F, to lead to a compound of formula (I/c), a particularcase of compounds of formula (I) ##STR11## in which X, R₁ and R" havethe same meaning as above, the isomers of which are optionally separatedby a conventional separation technique,

or to the action of an aldehyde of formula (VI)

    R"'--CHO                                                   (VI)

in which R"' is a linear or branched lower alkyl group, in the presenceof a reducing agent such as sodium borohydride, sodium cyanoborohydride,hydrogen Raney nickel or formic acid, to lead to a compound of formula(I/d) ##STR12## in which X, R₁ and R'" have the same meaning as above,the isomers of which are optionally separated by a conventionalseparation technique,

2/or with:

4-hydroxymethylpiperidine of formula (VII): ##STR13## to lead to acompound of formula (VIII): ##STR14## in which X has the same meaning asabove, the isomers of which are optionally separated by a conventionalseparation technique, which is submitted to the action of tosyl chloride(Cl-Tos), to lead to a compound of formula (IX): ##STR15## in which Xhas the same meaning as above, which is reacted:

either with a compound of formula (X): ##STR16## in which R₅ has thesame meaning as in formula (I), to lead to a compound of formula (I/e),a particular case of compounds of formula (I) ##STR17## in which X andR₅ have the same meaning as above, the isomers of which are optionallyseparated by a conventional separation technique,

or with a piperazine of formula (XI): ##STR18## in which Ra represents ahydrogen atom or a phenyl group, unsubstituted or substituted by one ormore halogen atoms, or alkyl (C₁ -C₆) or alkoxy (C₁ -C₆) groups, to leadto a compound of formula (I/f), a particular case of compounds offormula (I): ##STR19## in which X and Ra have the same meaning as above,the isomers of which are of which are optionally separated by aconventional separation technique, the compounds (I/a), (I/b), (I/c),(I/d), (I/e) and (I/f) are purified by a conventional purificationtechnique and are converted if desired into their addition salts with apharmaceutically acceptable acid.

The compounds of formula (I) possess valuable pharmacologicalproperties.

Binding tests showed that the compounds of the invention behaved as verypowerful ligands for 5-HT_(1A) receptors, with an agonist or antagonistaction on the central nervous system.

The compounds of the invention, therefore, find an application in thetreatment of stress (Neuropharmac., 1989, 25, (5) 471-476), anxiety,depression, schizophrenia and pain (Pharmacology and Toxicology, 1989,64 3-5), (Drugs of the Future, 1988, 13 (5) 429-437), (J. Neural.Transm. 1988, 74, 195-198).

Compounds which act on the 5-HT_(1A) receptors can also modify eatingand sexual behavior (J. Receptor Research, 1988 8, 59-81).

The subject of the present invention is also pharmaceutical compositionscontaining as active principle at least one compound of general formula(I) or one of their addition salts with a pharmaceutically acceptableacid, alone or in combination with one or more inert non-toxicexcipients or vehicles.

Among the pharmaceutical compositions according to the invention canparticularly be mentioned those which are suitable for oral, parenteral,or nasal administration, tablets or pills, sublingual tablets, capsules,suppositories, creams, dermal gels, etc.

The effective dosage varies according to the age and the weight of thepatient, the nature and severity of the affection as well as the routeof administration. This can be oral, nasal, rectal, or parenteral. Ingeneral the unit dosage ranges between 0.5 and 500 mg for one treatmentin 1 to 3 doses in 24 hours.

The following examples illustrate the invention

EXAMPLE 1 1-(Benzothiazol-2-yl)-4-Aminomethylpiperidine Hydrochloride

85 g of 4-aminomethylpiperidine are placed, at room temperature, in 750ml of anhydrous toluene in the presence of 103 g of potassium carbonateand of 125 g of 2-chlorobenzothiazole. This mixture is subjected toreflux for 8 hours, then filtered and the solution evaporated undervacuum.

The residue is taken up in ethanol and after an addition of excesshydrochloric ether, the precipitate formed is spun down and washed withether. The expected product is obtained after recrystallization fromethanol.

Melting point: 155-160° C.

    ______________________________________                                        Elemental microanalysis:                                                              C %    H %    N %      S %  Cl %                                      ______________________________________                                        Calculated:                                                                             48.75    5.98   13.12  10.01                                                                              22.14                                   Found:    48.85    5.73   13.10  10.24                                                                              22.48                                   ______________________________________                                    

EXAMPLE 2 1-Benzoxazol-2-yl)-4-Aminomethylpiperidine

45 g of 4-aminomethylpiperidine are placed, at room temperature, in 500ml of anhydrous toluene in the presence of 55 g of potassium carbonate.50 g of 2-chlorobenzoxazole are then added at 5° C.

The mixture is heated for 2 hours at 80° C. then filtered, and thesolution evaporated under vacuum.

The residue is taken up in 100 ml of ethanol, and after an addition ofexcess hydrochloric ether, the precipitate formed is spun down thenwashed with ether. This precipitate is taken up in a liter of 1 Ncaustic soda. The expected product is then extracted withdichloromethane. After drying, the organic phase is filtered andevaporated. The oil thus obtained is purified by chromatography onsilica gel (eluting solvent: dichloromethane/methanol/ammonia: 9/1/0.1).

Melting point: 64-66° C.

    ______________________________________                                        Elemental microanalysis:                                                                C %        H %    N %                                               ______________________________________                                        Calculated: 67.51        7.41   18.17                                         Found:      67.43        7.53   17.76                                         ______________________________________                                    

EXAMPLE 3 1-(benzimidazol-2-yl)-4-aminomethylpiperidine

45 g of 4-aminomethylpiperidine are placed in 500 ml of anhydroustoluene in the presence of 55 g of potassium carbonate and of 50 g of2-chlorobenzimidazole. The mixture is subjected to reflux overnight.Aver evaporation and crystallization of the oily residue, the expectedproduct is obtained after washing with dichloromethane.

Melting point: 136-138° C.

    ______________________________________                                        Elemental microanalysis:                                                                C %        H %    N %                                               ______________________________________                                        Calculated: 67.80        7.88   24.33                                         Found:      67.32        7.90   24.28                                         ______________________________________                                    

EXAMPLE 4 1-(1-methylbenzimidazol-2-yl)-4-aminomethyl-piperidine

27 g of 4-aminomethylpiperidine are placed in 300 ml of anhydroustoluene in the presence of 33 g of potassium carbonate and of 33 g of1-methyl-2-chlorobenzimidazole. The mixture is subjected to reflux for48 hours. After evaporation, the residue is taken up in ether and anexcess of hydrochloric ether. The precipitate formed is spun down,washed with ether, and then taken up in 750 ml of water and 30% causticsoda is added to give a basic pH.

The expected product is then extracted with dichloromethane. Afterdrying, the organic phase is filtered and evaporated. The oil thusobtained is purified by chromatography on silica gel (eluting solvent:dichloromethane/methane/ammonia: 9/1/0.1).

Melting point: 106° C.

    ______________________________________                                        Elemental microanalysis:                                                                C %        H %    N %                                               ______________________________________                                        Calculated: 67.21        8.68   22.35                                         Found:      67.51        8.02   24.12                                         ______________________________________                                    

EXAMPLE 51-(benzothiazol-2-yl)-4[(1,4-Benzodioxan-2-yl)Methylaminomethyl]piperidinedihydrochloride Stage A: 1-(Benzothiazol-2-Yl)-4Aminomethylpiperidine

The compound of Example 1 is taken up in 1 N caustic soda. The expectedproduct is then obtained after extraction with dichloromethane. Afterdrying, the organic phase is filtered and evaporated. The oil thusobtained is taken up in boiling hexane. After cooling, the productcrystallizes.

Melting point: 65-70° C.

    ______________________________________                                        Elemental microanalysis:                                                                 C %  H %        N %    S %                                         ______________________________________                                        Calculated:  63.12  6.93       16.99                                                                              12.96                                     Found:       63.69  6.19       17.08                                                                              13.01                                     ______________________________________                                    

Stage B: 1-(Benzothiazol-2-yl)-4-[(1,4-Benzodioxan-2-yl)Methylaminomethyl]Piperidine Dihydrochloride

9 g of the compound prepared in stage A and 9 g of2-mesyloxymethyl-1,4-benzodioxane are placed in 100 ml of anhydrousacetonitrile in the presence of 10 g of potassium carbonate. The mixtureis subjected to reflux overnight, then filtered, and the solutionevaporated under vacuum. The residue is taken up in 100 ml of 2 Nhydrochloric acid and the solution washed several times with ether. Theaqueous phase is then made alkaline with caustic soda and extracted withethyl acetate. After drying the organic phase, filtering, andevaporating, the oil thus obtained is purified by chromatography onsilica gel (eluting solvent: ether/methanol: 95/5). The expected productis obtained after addition of hydrochloric ether and precipitation andrecrystallization from ethanol

Melting point: 263° C.

    ______________________________________                                        Elemental microanalysis:                                                              C %    H %    N %      S %  Cl %                                      ______________________________________                                        Calculated:                                                                             56.41    5.81   8.97   6.84 15.14                                   Found:    56.01    5.78   8.98   6.92 15.04                                   ______________________________________                                    

EXAMPLE 6 1-(Benzothiazol-2-yl)-4[(Benzocyclobutan-1-yl)Methylaminomethyl]Piperidine Dihydrochloride

The expected product is obtained by proceeding as in Example 5 butreplacing the 2-mesyloxymethyl-1,4-benzodioxane at stage B by1-(mesyloxymethyl)benzocyclobutane (described in Tetrahedron, 1974,1053).

Melting point: 235° C.

    ______________________________________                                        Elemental microanalysis:                                                              C %    H %    N %      S %  Cl %                                      ______________________________________                                        Calculated:                                                                             60.54    6.24   9.63   7.35 16.25                                   Found:    60.56    6.26   9.78   7.56 16.28                                   ______________________________________                                    

EXAMPLE 7 1-(Benzothiazol-2-yl)-4-[1,4-Benzodioxan-2-yl)Acetamidomethyl]Piperidine Hydrochloride

At 0° C., 10 ml of oxalyl chloride are added to 2 g ofbenzodioxan-2-ylcarboxylic acid in solution in 50 ml of anhydrous ether.The mixture is left overnight at room temperature, and then evaporated.The residue is taken up in 10 ml of anhydrous toluene and 2.7 g of thecompound prepared at stage A of Example 5 are added at 0° C. Theprecipitate formed is filtered then taken up in ethanol and after anaddition of excess hydrochloric ether, the expected product is obtainedafter filtration and recrystallization from ethanol.

Melting point: 200-202° C.

    ______________________________________                                        Elemental microanalysis:                                                              C %    H %    N %      S %  Cl %                                      ______________________________________                                        Calculated:                                                                             59.25    5.42   9.42   7.19 7.95                                    Found:    58.95    5.51   9.34   7.07 7.85                                    ______________________________________                                    

EXAMPLE 8 1-(Benzothiazol-2-yl)-4-[(Chroman-2-yl)Methylaminomethyl]Piperidine Dihydrochloride

The expected product is obtained by proceeding as in Example 5 butreplacing the 2-mesyloxymethyl-1,4-benzodioxane at stage B by2-mesyloxymethylchromane.

Melting point: 240° C.

    ______________________________________                                        Elemental microanalysis:                                                              C %    H %    N %      S %  Cl %                                      ______________________________________                                        Calculated:                                                                             59.22    6.27   9.01   6.87 15.20                                   Found:    59.13    6.28   9.02   7.20 15.16                                   ______________________________________                                    

EXAMPLE 9 1-(Benzothiazol-2-yl)-4-[(7-Chloro-1,4-Benzodioxan-2-yl)Methylaminomethyl]Piperidine Dihydrochloride

The expected product is obtained by proceeding as in Example 5 butreplacing the 2-mesyloxymethyl-1,4-benzodioxane at stage B by2-mesyloxymethyl-7-chloro-1,4-benzodioxane.

Melting point: 280-282° C.

    ______________________________________                                        Elemental microanalysis:                                                              C %    H %    N %      S %  Cl %                                      ______________________________________                                        Calculated:                                                                             52.54    5.21   8.36   6.38 21.15                                   Found:    52.88    5.36   8.40   6.35 20.90                                   ______________________________________                                    

EXAMPLE 10 1-(Benzothiazol-2-yl)-4-[(5-Methoxy-1,4-Benzodioxan-2-yl)Methylaminomethyl]Piperidine Dihydrochloride

The expected product is obtained by proceeding as in Example 5 butreplacing the 2-mesyloxymethyl-1,4-benzodioxane at stage B by2-mesyloxymethyl-5-methoxy-1,4-benzodioxane described in J. Am. Chem.Soc. 1955, 373).

Melting point: 248-250° C.

    ______________________________________                                        Elemental microanalysis:                                                              C %    H %    N %      S %  Cl %                                      ______________________________________                                        Calculated:                                                                             55.42    5.86   8.43   6.43 14.22                                   Found:    55.56    5.93   8.47   6.59 14.33                                   ______________________________________                                    

EXAMPLE 11 1-(Benzothiazol-2-yl)-4-[(3-Methyl-1,4-Benzodioxan-2-yl)Methylaminomethyl]Piperidine Dihydrochloride

The expected product is obtained by proceeding as in Example 5 but byreplacing the 2-mesyloxymethyl-1,4-benzodioxane at stage B by2-mesyloxymethyl-3-methyl-1,4-benzodioxane.

Melting point: 220-228° C.

    ______________________________________                                        Elemental microanalysis:                                                              C %    H %    N %      S %  Cl %                                      ______________________________________                                        Calculated:                                                                             57.26    6.06   8.71   6.65 14.70                                   Found:    57.33    6.26   8.83   6.75 14.71                                   ______________________________________                                    

EXAMPLE 12 1-(Benzothiazol-2-yl)-4-[N-(1,4-Benzodioxan-2-yl)Methyl]-N-(Methyl)Aminomethyl]Piperidine Dihydrochloride

Caustic soda is added to 1 g of the product prepared in Example 5 togive the corresponding base, which is taken up in 7.5 ml of anhydrousacetonitrile. After the addition of 1 ml of a solution of 40%formaldehyde and of 250 mg of sodium cyanoborohydride, the mixture isleft under stirring for 15 minutes at room temperature. 1 ml of aceticacid is then added and the mixture is again stirred for 15 minutes atroom temperature. After evaporating the solvent, adding 10 ml of 2 Ncaustic soda and extraction with ether, the organic phase is extractedwith 3 N hydrochloric acid. The aqueous phase thus obtained is madealkaline with caustic soda and again extracted with ether. After dryingand filtration, the solvent is evaporated. The expected product isobtained by precipitating the dihydrochloride in hydrochloric ether.

Melting point: 165° C.

    ______________________________________                                        Elemental microanalysis:                                                              C %    H %    N %      S %  Cl %                                      ______________________________________                                        Calculated:                                                                             57.26    6.06   8.71   6.65 14.70                                   Found:    57.21    6.12   8.46   6.61 14.39                                   ______________________________________                                    

Examples 13 and 14 1-(Benzothiazol-2-yl)-4-[Benzofuran-2-yl)Methylaminomethyl]Piperidine Dihydrochloride

The expected product is obtained by proceeding as in Example 5 butreplacing the 2-mesyloxymethyl-1,4-benzodioxane at stage B by2-chloromethylbenzofuran, and purification of the oil by chromatographyon silica gel (eluting solvent: ether).

Melting point: 241-242° C.

    ______________________________________                                        Elemental microanalysis:                                                              C %    H %    N %      S %  Cl %                                      ______________________________________                                        Calculated:                                                                             58.66    5.59   9.33   7.12 15.74                                   Found:    58.52    5.67   9.41   7.08 15.69                                   ______________________________________                                    

EXAMPLE 14 1-(Benzothiazol-2-yl)-4-[Di[(Benzofuran-2-yl)Methyl]Aminomethyl]Piperidine Dihydrochloride

Caustic soda is added to 1 g of the product prepared in Example 13 togive the corresponding base which is taken up in anhydrous acetonitrile.By proceeding as in stage B of Example 5 but replacing2-mesyloxymethyl-1,4-benzodioxane by 2-chloromethylbenzofuran, theexpected product is obtained.

Melting point: 183-185° C.

    ______________________________________                                        Elemental microanalysis:                                                              C %    H %    N %      S %  Cl %                                      ______________________________________                                        Calculated:                                                                             64.13    5.38   7.24   5.52 12.21                                   Found:    64.03    5.48   7.15   5.52 12.26                                   ______________________________________                                    

EXAMPLE 15 1-(Benzothiazol-2-yl)-4-[[2-(2methoxyphenoxy)Ethyl]Aminomethyl]Piperidine Dihydrochloride

The expected product is obtained by proceeding as in Example 5 butreplacing the 2-mesyloxymethyl-1,4-benzodioxane at stage B by1-tosyloxy-2-(2-methoxyphenoxy)ethane.

Melting point: 220° C.

    ______________________________________                                        Elemental microanalysis:                                                              C %    H %    N %      S %  Cl %                                      ______________________________________                                        Calculated:                                                                             56.17    6.21   8.93   6.82 15.07                                   Found:    56.42    6.23   9.05   6.95 15.33                                   ______________________________________                                    

EXAMPLE 161-(Benzothiazol-2-yl)-4-[(8-Methoxy-1,4-Benzodioxan-2-yl)-Methylaminomethyl-9Piperidine Dihydrochloride

The expected product is obtained by proceeding as in Example 5 butreplacing the 2-mesyloxymethyl-1,4-benzodioxane at stage B by2-tosyloxymethy1-8-methoxy-1,4-benzodioxane (described in Patent EP210,581).

Melting Point: 265-268° C.

    ______________________________________                                        Elemental microanalysis:                                                              C %    H %    N %      S %  Cl %                                      ______________________________________                                        Calculated:                                                                             55.42    5.86   8.43   6.43 14.22                                   Found:    55.54    6.06   8.85   6.57 14.26                                   ______________________________________                                    

Example 17 1-Benzothiazol-2-yl)-4-[(6-chloro-1,4-Benzodioxan-2-yl)Methylaminomethyl]Piperidine Dihydrochloride

The expected product is obtained by proceeding as in Example 5 butreplacing the 2-mesyloxymethyl-1,4-benzodioxane at stage B by2-tosyloxymethyl-6-chloro-1,4-benzodioxane (described in Patent BE843,995).

Melting point: 260-264° C.

    ______________________________________                                        Elemental microanalysis:                                                              C %    H %    N %      S %  Cl %                                      ______________________________________                                        Calculated:                                                                             52.54    5.21   8.36   6.38 21.25                                   Found:    52.37    5.14   8.40   6.55 21.24                                   ______________________________________                                    

EXAMPLE 18 1-(Benzothiazol-2-yl)-4-[(7-Methyl-2,3-Dihydrobenzofuran-2yl)Methylaminomethyl]Piperidine Dihydrochloride

The expected product is obtained by proceeding as in Example 5 butreplacing the 2-mesyloxymethyl-1,4-benzodioxane at stage B by2-tosyloxymethyl-7-methyl-2,3-dihydrobenzofuran.

Melting point: 222-224° C.

    ______________________________________                                        Elemental microanalysis:                                                              C %    H %    N %      S %  Cl %                                      ______________________________________                                        Calculated:                                                                             59.22    6.27   9.01   6.87 15.20                                   Found:    59.09    6.22   9.05   6.93 15.25                                   ______________________________________                                    

EXAMPLE 19 1-(Benzothiazol-2-yl)-4-(7-Chloro-2,3-Dihydrobenzofuran-2-yl)Methylaminomethyl]Piperidine Dihydrochloride

The expected product is obtained by proceeding as in Example 5 butreplacing the 2-mesyloxymethyl-1,4-benzodioxane at stage B by2-tosyloxymethyl-7-chloro-2,3-dihydrobenzofuran.

Melting point: 212-214° C.

    ______________________________________                                        Elemental microanalysis:                                                              C %    H %    N %      S %  Cl %                                      ______________________________________                                        Calculated:                                                                             54.27    5.38   8.63   6.59 21.84                                   Found:    53.97    5.45   8.76   6.66 21.98                                   ______________________________________                                    

EXAMPLE 20 1-(Benzothiazol-2-yl)-4[(7-Fluoro-2,3-Dihydrobenzofuran-2-yl)Methylaminomethyl]Piperidine Dihydrochloride

The expected product is obtained by proceeding as in Example 5 butreplacing the 2-mesyloxymethyl-1,4-benzodioxane at stage B by2-tosyloxymethyl-7-fluoro-2,3dihydrobenzofuran.

Melting point: 205-208° C.

    ______________________________________                                        Elemental microanalysis:                                                              C %    H %    N %      S %  Cl %                                      ______________________________________                                        Calculated:                                                                             56.17    5.57   8.93   6.82 15.07                                   Found:    55.95    5.59   9.15   6.78 15.31                                   ______________________________________                                    

EXAMPLE 211-(Benzothiazol-2-yl)-4-[(7-Isopropyl-2,3-Dihydrobenzofuran-2-yl)Methylaminomethyl]Piperidine Dihydrochloride

The expected product is obtained by proceeding as in Example 5 butreplacing the 2-mesyloxymethyl-1,4-benzodioxane at stage B by2-tosyloxymethyl-7-isopropyl-2,3-dihydrobenzofuran.

Melting point: 218-220° C.

    ______________________________________                                        Elemental microanalysis:                                                              C %    H %    N %      S %  Cl %                                      ______________________________________                                        Calculated:                                                                             60.72    6.74   8.50   6.48 14.34                                   Found:    60.56    6.49   8.62   6.50 14.39                                   ______________________________________                                    

EXAMPLE 221-(Benzothiazol-2-yl)-4-[(5-Fluoro-2,3-Dihydrobenzofuran-2-yl)Methylaminomethyl]Piperidine Dihydrochloride.

The expected product is obtained by proceeding as in Example 5 butreplacing the 2-mesyloxymethyl-1,4-benzodioxane at stage B by2-tosyloxymethyl-5-fluoro-2,3-dihydrobenzofuran.

Melting point: 223-228° C.

    ______________________________________                                        Elemental microanalysis:                                                              C %    H %    N %      S %  Cl %                                      ______________________________________                                        Calculated:                                                                             56.17    5.57   8.93   6.82 15.07                                   Found:    56.16    5.57   8.91   6.83 15.02                                   ______________________________________                                    

EXAMPLE 23 1-(Benzothiazol-2-yl)-4-[(2,3-Dihydrobenzofuran-2yl)Methylaminomethyl]Piperidine Dihydrochloride

The expected product is obtained by proceeding as in Example 5 butreplacing the 2-mesyloxymethyl-1,4-benzodioxane at stage B by2-tosyloxymethyl-2,3-dihydrobenzofuran.

Melting Point: 230-235° C.

    ______________________________________                                        Elemental microanalysis:                                                              C %    H %    N %      S %  Cl %                                      ______________________________________                                        Calculated:                                                                             58.40    6.02   9.29   7.09 15.67                                   Found:    58.46    5.78   9.18   7.21 15.72                                   ______________________________________                                    

EXAMPLE 24 1(Benzothiazol-2-yl)-4-[(7-Methoxy-1,4-Benzodioxan-2-yl)Methylaminomethyl]Piperidine Dihydrochloride

The expected product is obtained by proceeding as in Example 5 butreplacing the 2-mesyloxymethyl-1,4-benzodioxane at stage B by2-tosyloxymethyl-7-methoxy-1,4-benzodioxane (described in J. Med. Chem.,1965, 8, 446).

Melting point: 267-270° C.

    ______________________________________                                        Elemental microanalysis:                                                              C %    H %    N %      S %  Cl %                                      ______________________________________                                        Calculated:                                                                             55.42    5.86   8.43   6.43 14.22                                   Found:    55.11    5.87   8.63   6.72 14.17                                   ______________________________________                                    

EXAMPLE 25 1-(Benzothiazol-2-yl)-4-[(6-Methoxy-1,4-Benzodioxan-2-yl)Methylaminomethyl]Piperidine dihydrochloride

The expected product is obtained by proceeding as in Example 5 butreplacing the 2-mesyloxymethyl-1,4-benzodioxane at stage B by2-tosyloxymethyl-6-methoxy1,4-benzodioxane (described in J. Med. Chem.,1965, 8, 446).

Melting point: 235-240° C.

    ______________________________________                                        Elemental microanalysis:                                                              C %    H %    N %      S %  Cl %                                      ______________________________________                                        Calculated:                                                                             55.42    5.86   8.43   6.43 14.22                                   Found:    55.25    5.67   7.89   6.51 14.12                                   ______________________________________                                    

EXAMPLE 26 1-(Benzothiazol-2-yl)-4-[(Benzothiazol-2-yl)Aminomethyl]Piperidine Dihydrochloride Elemental microanalysis: EXAMPLE26 1-(Benzothiazol-2-yl)-4-[(Benzothiazol-2-yl) Aminomethyl]PiperidineDihydrochloride

The expected product is obtained by proceeding as in Example 1 butplacing 1 unit of 4-aminomethylpiperidine in anhydrous toluene for everytwo units of 2-chlorobenzothiazole at room temperature.

Melting point: 190-195° C.

    ______________________________________                                        Elemental microanalysis:                                                              C %    H %    N %      S %  Cl %                                      ______________________________________                                        Calculated:                                                                             52.98    4.89   12.36  14.14                                                                              15.64                                   Found:    53.04    4.85   12.48  14.20                                                                              15.76                                   ______________________________________                                    

EXAMPLE 27 1-(Benzothiazol-2-yl)-4-[(3-Phenoxypropyl)-Aminomethyl]Piperidine Dihydrochloride

The expected product is obtained by proceeding as in Example 5 butreplacing the 2-mesyloxymethyl-1,4-benzodioxane at stage B by(1-bromo-3-phenoxy)propane.

Melting point: 247-249° C. Elemental microanalysis:

    ______________________________________                                        Elemental microanalysis:                                                              C %    H %    N %      S %  Cl %                                      ______________________________________                                        Calculated:                                                                             58.14    6.43   9.25   7.06 15.60                                   Found:    58.34    6.38   9.29   7.16 15.58                                   ______________________________________                                    

EXAMPLE 28 1-(Benzothiazol-2-yl)-4-[(6-Fluoro-1,4-Benzodioxan-2-yl)Methylaminomethyl]Piperidine Dihydrochloride

The expected product is obtained by proceeding as in Example 5 butreplacing the 2-mesyloxymethyl-1,4-benzodioxane at stage B by2-tosyloxymethyl-6-fluorobenzodioxane (described in Patent BE 843,995).

Melting point: 260-265° C.

    ______________________________________                                        Elemental microanalysis:                                                              C %    H %    N %      S %  Cl %                                      ______________________________________                                        Calculated:                                                                             54.32    5.39   8.64   6.59 11.58                                   Found:    54.65    5.40   8.41   6.56 14.44                                   ______________________________________                                    

EXAMPLE 29 1(Benzothiazol-2-yl)-4-[[2-(2,6-Dimethoxyphenoxy)Ethyl]Aminomethyl]Piperidine Dihydrochloride

The expected product is obtained by proceeding as in Example 5 butreplacing the 2-mesyloxymethyl-1,4-benzodioxane at stage B by1-bromo-2-(2,6-dimethoxy-phenoxy)ethane.

Melting point: 176-180° C.

    ______________________________________                                        Elemental microanalysis:                                                              C %    H %    N %      S %  Cl %                                      ______________________________________                                        Calculated:                                                                             55.20    6.24   8.40   6.41 14.17                                   Found:    54.90    5.77   8.23   6.65 14.11                                   ______________________________________                                    

EXAMPLE 30 1-(Benzothiazol-2-yl)-4-[[2-(4-Methoxyphenoxy)Ethyl[Aminomethyl]Piperidine dihydrochloride

The expected product is obtained by proceeding as in Example 5 butreplacing the 2-mesyloxymethyl-1,4-benzodioxane at stage B by1-bromo-2-(4-methoxyphenoxy)ethane.

Melting point: 203° C.

    ______________________________________                                        Elemental microanalysis:                                                              C %    H %    N %      S %  Cl %                                      ______________________________________                                        Calculated:                                                                             56.17    6.21   8.93   6.82 15.07                                   Found:    56.17    6.21   8.99   7.03 14.98                                   ______________________________________                                    

EXAMPLE 31 1-(Benzothiazol-2-yl)-4-[[2-(3-Methoxyphenoxy)ethyl]Aminomethyl]Piperidine Dihydrochloride

The expected product is obtained by proceeding as in Example 5 butreplacing the 2-mesyloxymethyl-1,4-benzodioxane at stage B by1-bromo-2-(3-methoxyphenoxy)-ethane.

Melting point: 211-213° C.

    ______________________________________                                        Elemental microanalysis:                                                              C %    H %    N %      S %  Cl %                                      ______________________________________                                        Calculated:                                                                             56.17    6.21   8.93   6.82 15.07                                   Found:    56.01    6.04   8.92   6.84 15.12                                   ______________________________________                                    

EXAMPLE 32 1-(Benzothiazol-2-yl)-4-[[(5-chloro-1,4-Benzodioxan-2-yl)Methylaminomethyl]Piperidine dihydrochloride

The expected product is obtained by proceeding as in Example 5 butreplacing the 2-mesyloxymethyl-1,4-benzodioxane at stage B by2-tosyloxymethyl-5-chloro-1,4-benzodioxane (described in J. Med. Chem.,1965, 8, 446).

Melting point: 235-238° C.

    ______________________________________                                        Elemental microanalysis:                                                              C %    H %      N %     S %  Cl %                                     ______________________________________                                        Calculated:                                                                             52.54    5.21     8.36  6.38 21.15                                  Found:    52.77    5.25     8.32  6.51 21.14                                  ______________________________________                                    

EXAMPLE 33 1-(Benzothiazol-2-yl)-4-[(5,6-Dichloro-1,4-Benzodioxan-2-yl)Methylaminomethyl]Piperidine Dihydrochloride

The expected product is obtained by proceeding as in Example 5 butreplacing the 2-mesyloxymethyl-1,4-benzodioxane at stage B by2-tosyloxymethyl-5,6-dichloro-1,4-benzodioxane (described in J. Med.Chem., 1965, 8, 446).

Melting point: 269-272° C.

    ______________________________________                                        Elemental microanalysis:                                                              C %    H %      N %     S %  Cl %                                     ______________________________________                                        Calculated:                                                                             49.18    4.69     7.82  5.97 26.39                                  Found:    48.89    4.81     7.69  6.00 26.64                                  ______________________________________                                    

EXAMPLE 34 1-(Benzothiazol-2-yl)-4-[[2-(Benzodioxan-5-yloxy)Ethyl]Aminomethyl]Piperidine Dihydrochloride

The expected product is obtained by proceeding as in Example 5 butreplacing the 2-mesyloxymethyl-1,4-benzodioxane at stage B by1-chloro-2-(1,4-benzodioxan-5-yloxy) ethane (described in Patent FR1,343,644).

Melting point: 176-178° C.

    ______________________________________                                        Elemental microanalysis:                                                              C %    H %      N %     S %  Cl %                                     ______________________________________                                        Calculated:                                                                             55.42    5.86     8.43  6.43 14.22                                  Found:    55.22    6.48     8.20  6.45 14.23                                  ______________________________________                                    

EXAMPLE 35 1-(Benzoxazol-2-yl)-4-[(1,4-Benzodioxan-2-ylMethylaminomethyl[Piperidine dihydrochloride

The expected product is obtained by proceeding as in Example 5 butreplacing the 2-mesyloxymethyl-1,4-benzodioxane at stage B by2-tosyloxymethyl-1,4-benzodioxane and the1-(benzothiazol-2-yl)-4-aminomethylpiperidine by1-(benzoxazol-2-yl)-4-aminomethylpiperidine prepared in Example 2.

Melting point: 260-261° C.

    ______________________________________                                        Elemental microanalysis:                                                                 C %  H %        N %    Cl %                                        ______________________________________                                        Calculated:  58.41  6.02       9.29 15.67                                     Found:       58.37  6.07       9.40 15.59                                     ______________________________________                                    

Example 36 1-(Benzothiazol-2-yl)-4-[(2-Phenoxyethyl)-Aminomethyl[Piperidine Dihydrochloride

The expected product is obtained by proceeding as in Example 5 butreplacing the 2-mesyloxymethyl-1,4-benzodioxane at stage B byβ-bromophenetol.

Melting point: 240-242° C.

    ______________________________________                                        Elemental microanalysis:                                                              C %    H %      N %     S %  Cl %                                     ______________________________________                                        Calculated:                                                                             57.27    6.18     9.54  7.28 16.10                                  Found:    57.41    6.08     9.57  7.39 16.41                                  ______________________________________                                    

Example 37 1-(Benzothiazol-2-yl)-4[[2-(2-Chlorophenoxy)ethyl]Aminomethyl]Piperidine Dihydrochloride

The expected product is obtained by proceeding as in Example 5 butreplacing the 2-mesyloxymethyl-1,4-benzodioxane at stage B by1-bromo-2-(2-chlorophenoxy)ethane.

Melting point: 225-228° C.

    ______________________________________                                        Elemental microanalysis:                                                              C %    H %      N %     S %  Cl %                                     ______________________________________                                        Calculated:                                                                             53.11    5.52     8.85  6.75 22.40                                  Found:    53.25    5.53     8.80  6.15 22.07                                  ______________________________________                                    

EXAMPLE 38 1-(Benzothiazol-2-yl)-4-[[2-(3-chlorophenoxy)Ethyl]Aminomethyl]Piperidine Dihydrochloride

The expected product is obtained by proceeding as in Example 5 butreplacing the 2-mesyloxymethyl-1,4-benzodioxane at stage B by1-bromo-2-(3-chlorophenoxy)ethane.

Melting point: 185-190° C.

    ______________________________________                                        Elemental microanalysis:                                                              C %    H %      N %     S %  Cl %                                     ______________________________________                                        Calculated:                                                                             53.11    5.52     8.85  6.75 22.40                                  Found:    53.08    5.59     8.91  6.47 22.42                                  ______________________________________                                    

EXAMPLE 39 1-(Benzothiazol-2-yl)-4-[[2-(4-Chlorphenoxy)Ethyl]Aminomethyl]Piperidine Dihydrochloride

The expected product is obtained by proceeding as in Example 5 butreplacing the 2-mesyloxymethyl-1,4-benzodioxane at stage B by1-bromo-2-(4-chlorophenoxy)ethane.

Melting point: 255-260° C.

    ______________________________________                                        Elemental microanalysis:                                                              C %    H %      N %     S %  Cl %                                     ______________________________________                                        Calculated:                                                                             53.11    5.52     8.85  6.75 22.40                                  Found:    53.09    5.42     8.86  6.72 22.04                                  ______________________________________                                    

EXAMPLE 40 1-Benzimidazol-2-yl)-4-[(1,4-Benzodioxan-2-yl)Methylaminomethyl]Piperidine Dihydrochloride

The expected product is obtained by proceeding as in Example 5 butreplacing the 2-mesyloxymethyl-1,4-benzodioxane by2-tosyloxymethyl-1,4-benzodioxane and the1-(benzothiazol-2-yl)-4-aminomethylpiperidine by1-(benzimidazol-2-yl)-4-aminomethylpiperidine prepared in Example 3.

Melting point: >260° C.

    ______________________________________                                        Elemental microanalysis:                                                              C %    H %      N %     S %  Cl %                                     ______________________________________                                        Calculated:                                                                             58.54    6.25     12.41 15.71                                       Found     58.87    6.22     12.37 15.79                                       ______________________________________                                    

EXAMPLE 41 1-(Benzothiazol-2-yl)-4-[[2-(2,6-Dichlorophenoxy)ethyl]Aminomethyl]Piperidine Dihydrochloride

The expected product is obtained by proceeding as in Example 5 butreplacing the 2-mesyloxymethyl-1,4-benzodioxane at stage B by1-bromo-2-(2,6-dichlorophenoxy)ethane.

Melting point: 212-216° C.

    ______________________________________                                        Elemental microanalysis:                                                              C %    H %      N %     S %  Cl %                                     ______________________________________                                        Calculated:                                                                             49.52    4.95     8.25  6.30 27.84                                  Found:    49.23    5.05     8.24  6.63 27.94                                  ______________________________________                                    

EXAMPLE 42 1-(Benzoxazol-2-yl)-4-[(8-Methoxy-1,4-Benzodioxan-2-yl)Methylaminomethyl]Piperidine dihydrochloride

The expected product is obtained by proceeding as in Example 35 butreplacing the 2-tosyloxymethyl-1,4benzodioxane at stage B by2-tosyloxymethyl-8-methoxy1,4-benzodioxane (described in Patent EP210,581).

Melting point: 226-228° C.

    ______________________________________                                        Elemental microanalysis:                                                              C %    H %      N %     S %  Cl %                                     ______________________________________                                        Calculated:                                                                             57.27    6.06     8.71  14.70                                       Found:    56.99    5.98     8.62  14.81                                       ______________________________________                                    

EXAMPLE 43 1-Benzimidazol-2-yl)-4-[(2,3-Dihydrobenzofuran-2-yl)Methylaminomethyl]Piperidine Dihydrochloride

The expected product is obtained by proceeding as in Example 40 butreplacing the 2-tosyloxymethyl-1,4-benzodioxane by2-tosyloxymethyl-2,3-dihydrobenzofuran.

Melting point: 241-245° C.

    ______________________________________                                        Elemental microanalysis:                                                                 C %  H %        N %    Cl %                                        ______________________________________                                        Calculated:  60.69  6.48       12.87                                                                              16.29                                     Found:       60.61  6.52       12.93                                                                              16.24                                     ______________________________________                                    

EXAMPLE 44 1-Benzoxazol-2-yl)-4-[[2-(2-Methoxyphenoxy)-Ethyl]Aminomethyl]Piperidine Dihydrochloride

The expected product is obtained by proceeding as in Example 35 butreplacing the 2-tosyloxymethyl-1,4-benzodioxane by1-tosyloxy-2-(2-methoxyphenoxy)ethane.

Melting point: 200-202° C.

    ______________________________________                                        Elemental microanalysis:                                                                 C %  H %        N %    Cl %                                        ______________________________________                                        Calculated:  58.15  6.43       9.25 15.60                                     Found:       57.97  6.65       9.10 15.47                                     ______________________________________                                    

EXAMPLE 45 1-(Benzimidazol-2-yl)-4-[[2-(2-Methoxyphenoxy)ethyl]Aminomethyl]Piperidine dihydrochloride

The expected product is obtained by proceeding as in Example 40 butreplacing the 2-tosyloxymethyl-1,4-benzodioxane by1-tosyloxy-2-(2-methoxyphenoxy)ethane.

Melting point: 275-280° C.

    ______________________________________                                        Elemental microanalysis:                                                                 C %  H %        N %    Cl %                                        ______________________________________                                        Calculated:  58.41  6.46       12.38                                                                              15.67                                     Found:       58.13  6.69       11.96                                                                              15.62                                     ______________________________________                                    

EXAMPLE 46 1-(Benzimidazol-2-yl)-4-[(8-Methoxy-1,4-Benzodioxan-2-yl)Methylaminomethyl]Piperidine Dihydrochloride

The expected product is obtained by proceeding as in Example 40 butreplacing the 2-tosyloxymethyl-1,4-benzodioxane by2-tosyloxymethyl-8-methoxy-1,4-benzodioxane (described in Patent EP210,581).

Melting point: 315-317° C.

    ______________________________________                                        Elemental microanalysis:                                                                 C %  H %        N %    Cl %                                        ______________________________________                                        Calculated:  57.38  6.28       11.64                                                                              14.73                                     Found:       57.34  6.32       11.51                                                                              14.59                                     ______________________________________                                    

EXAMPLE 471-(1-Methylbenzimidazol-2-yl)-4-[(8-Methoxy-1,4-Benzodioxan-2-yl]Methylaminomethyl]Piperidine Dihydrochloride

The expected product is obtained by proceeding as in Example 5 butreplacing the 2-mesyloxymethyl-1,4-benzodioxane by2-tosyloxymethyl-8-methoxy-1,4-benzodioxane (described in Patent EP210,581), and the 1-(benzothiazol-2-yl)-4-aminomethylpiperidine by1-(1-methylbenzimidazol-2-yl)-4-aminomethylpiperidine obtained inExample 4.

Melting point: 265-267° C.

    ______________________________________                                        Elemental microanalysis:                                                                 C %  H %        N %    Cl %                                        ______________________________________                                        Calculated:  58.18  6.51       11.31                                                                              14.31                                     Found:       58.28  6.69       11.15                                                                              14.38                                     ______________________________________                                    

EXAMPLE 48 b 1-(1-Methylbenzimidazol-2-yl)-4-[(1,4-Benzodioxan-2-yl)Methylaminomethyl]Piperidine Dihydrochloride.

The expected product is obtained by proceeding as in Example 47 butreplacing the 2-tosyloxymethyl-8- methoxy-1,4-benzodioxane by2-tosyloxymethyl-1,4-benzodioxane.

Melting point: 253-255° C.

    ______________________________________                                        Elemental microanalysis:                                                                 C %  H %        N %    Cl %                                        ______________________________________                                        Calculated:  59.36  6.50       12.04                                                                              15.23                                     Found:       59.55  6.70       11.95                                                                              15.34                                     ______________________________________                                    

EXAMPLE 49 1-(Benzothiazol-2-yl)-4-[[3-(2,6-Dimethoxyphenoxy)propyl]Aminomethyl]Piperidine Dihydrochloride.

The expected product is obtained by proceeding as in Example 5 butreplacing the 2-mesyloxymethyl-1,4-benzodioxane at stage B by1-bromo-3-(2,6-dimethoxyphenoxy)propane.

Melting point: 205-207° C.

    ______________________________________                                        Elemental microanalysis:                                                              C %    H %      N %     S %  Cl %                                     ______________________________________                                        Calculated:                                                                             56.03    6.46     8.17  6.23 13.78                                  Found:    55.71    6.71     8.06  6.35 13.90                                  ______________________________________                                    

EXAMPLE 50 1-(1-Methylbenzimidazol-2-yl)-4-[[2-(2-Methoxyphenoxy)ethyl]Aminomethyl]Piperidine Dihydrochlorine

The expected product is obtained by proceeding as in Example 47 butreplacing the 2-tosyloxymethyl-8-methoxy-1,4-benzodioxane at stage B by1-tosyloxy-2-(2-methoxyphenoxy)ethane.

Melting point: 270-274° C.

    ______________________________________                                        Elemental microanalysis:                                                                 C %  H %        N %    Cl %                                        ______________________________________                                        Calculated:  59.10  6.90       11.99                                                                              15.17                                     Found:       59.24  7.01       12.01                                                                              15.10                                     ______________________________________                                    

EXAMPLE 5 1-(Benzothiazol-2-yl)-4-[(8-Chloro-1,4-Benzodioxan-2-yl)Methylaminomethyl]Piperidine Dihydrochloride

The expected product is obtained by proceeding as in Example 5 butreplacing the 2-mesyloxymethyl-1,4-benzodioxane at stage B by2-tosyloxymethyl-8-methoxy1,4-benzodioxane (described in J. Med. Chem.1965, 8, 446).

Melting point: 220-222° C.

    ______________________________________                                        Elemental microanalysis:                                                              C %    H %      N %     S %  Cl %                                     ______________________________________                                        Calculated:                                                                             52.54    5.21     8.36  6.44 21.15                                  Found:    52.63    5.24     8.03  6.38 21.08                                  ______________________________________                                    

The expected product is obtained by proceeding as in Example 5 butreplacing the 2-mesyloxymethyl-1,4-benzodioxane at stage B by2-tosyloxyethyl-1,4-benzodioxane.

Melting point: 260-264° C.

    ______________________________________                                        Elemental microanalysis:                                                              C %    H %      N %     S %  Cl %                                     ______________________________________                                        Calculated:                                                                             57.26    6.06     8.71  6.65 14.70                                  Found:    57.16    5.95     8.62  6.86 14.81                                  ______________________________________                                    

EXAMPLE 53 N,N-Di-[[1-(Benzothiazol-2-yl)Piperidine-4-yl]methyl]AmineTrichlorohydride Stage A:1-(Benzothiazol-2-yl)-4-Hydroxymethylpiperidine

30 g of 4-hydroxymethylpiperidine, 44 g of 2-chlorobenzothiazole and 72g of potassium carbonate are reacted in 600 ml of acetonitrile underreflux overnight. After filtration and evaporation of the solvent, theresidue is taken up in 200 ml of ethyl acetate and extracted with 1 Nhydrochloric acid. The aqueous phase is made alkaline with caustic sodaand extracted with dichloromethane. The expected product is obtained bydrying and evaporation.

Melting point: 76-80° C.

Stage B: 1-(Benzothiazol-2-yl)-4-Tosyloxymethylpiperidine

After dissolving the compound obtained at stage A in pyridine and addingan equivalent amount of tosyl chloride, the reaction mixture is stirredovernight at room temperature. The expected product is obtained afterwashing with diluted hydrochloric acid and with water.

Melting point: 184° C.

Stage C: N,N-Di[[1-Benzothiazol-2-yl)Piperidine-4-yl]Methyl]AmineTrihydrochloride

The expected product is obtained by proceeding as in Example 5 butreplacing the 2-mesyloxymethyl-1,4-benzodioxane by1-(benzothiazol-2-yl)-4-tosyloxymethylpiperidine obtained in thepreceding stage.

Melting point: 265-270° C.

    ______________________________________                                        Elemental microanalysis:                                                              C %    H %      N %     S %  Cl %                                     ______________________________________                                        Calculated:                                                                             53.19    5.84     11.93 10.92                                                                              18.12                                  Found:    53.62    5.96     11.92 10.90                                                                              17.72                                  ______________________________________                                    

EXAMPLE 54 1-(Benzoxazol-2-yl)-4-[(2,3-Dihydrobenzofuran-2-yl)Methylaminomethyl]Piperidine Dihydrochloride

The expected product is obtained by proceeding as in Example 35 butreplacing the 2-tosyloxymethyl-1,4-benzodioxane at stage B by2-tosyloxymethyl-2,3-dihydrobenzofuran.

Melting point: 228-230° C.

    ______________________________________                                        Elemental microanalysis:                                                                 C %  H %        N %    Cl %                                        ______________________________________                                        Calculated:  60.55  6.24       9.63 16.25                                     Found:       60.62  6.43       9.58 15.94                                     ______________________________________                                    

EXAMPLE 55 1-(Benzothiazol-2-yl)-4-[(5,8-Dimethoxy-1,4-Benzodioxan-2-yl)Methylaminomethyl]Piperidine Dihydrochloride

The expected product is obtained by proceeding as in Example 5 butreplacing the 2-mesyloxymethyl-1,4-benzodioxane at stage B by2-tosyloxymethyl-5,8-dimethoxy-1,4-benzodioxane (described in J. Chem.Soc., Perkin Trans. I, 1987, 2017-22).

Melting point: 240-245° C.

    ______________________________________                                        Elemental microanalysis:                                                              C %    H %      N %     S %  Cl %                                     ______________________________________                                        Calculated:                                                                             54.54    5.91     7.95  6.07 13.42                                  Found:    54.62    5.86     7.82  6.09 13.34                                  ______________________________________                                    

EXAMPLE 56 1-(2-Methoxyphenyl)-4-[[1-(Benzothiazol-2-yl)Piperidine-4-yl]Methyl]Piperazine

6 g of the compound described at stage B of Example 53, 2.9 g of1-(2-methoxyphenyl)piperazine and 4.8 g of potassium carbonate arereacted in 90 ml of acetonitrile under reflux overnight. Afterfiltration and evaporation of the solvents, the residue is taken up in20 ml of 2 N hydrochloric acid, and the solution is washed several timeswith ether. After making the aqueous phase alkaline with caustic soda itis extracted with methylene chloride. The expected product is obtainedafter drying and evaporating the solvent.

Melting point: 150-152° C.

    ______________________________________                                        Elemental microanalysis:                                                                 C %  H %        N %    S %                                         ______________________________________                                        Calculated:  68.21  7.16       13.26                                                                              7.59                                      Found:       68.15  7.32       13.33                                                                              7.51                                      ______________________________________                                    

EXAMPLE 571-(Benzothiazol-2-yl)-4-[2-[(Indol-3-yl)-Ethyl]Aminomethyl]PiperidineDihydrochloride

By proceeding as in Example 56 but replacing the1-(2-methoxyphenyl)piperazine by tryptamine, the expected product isobtained in its basic form, which is converted to dihydrochloride byaddition of hydrochloric ether, and crystallized in ethanol.

Melting point: 278-282° C.

    ______________________________________                                        Elemental microanalysis:                                                              C %    H %      N %     S %  Cl %                                     ______________________________________                                        Calculated:                                                                             59.61    6.09     12.09 6.92 15.30                                  Found     59.23    6.13     11.96 6.91 15.03                                  ______________________________________                                    

EXAMPLE 58 1-(Benzothiazol-2-yl)-4-]]2-(5-Methoxyindol-3-yl)Ethyl]Aminomethyl]Piperidine Dihydrochloride

The expected product is obtained by proceeding as in Example 57 butreplacing the tryptamine by 5-methoxytryptamine.

Melting point: 250-254° C.

    ______________________________________                                        Elemental microanalysis:                                                              C %    H %      N %     S %  Cl %                                     ______________________________________                                        Calculated:                                                                             58.29    6.32     11.33 6.48 14.34                                  Found:    58.48    6.36     11.25 6.53 14.13                                  ______________________________________                                    

EXAMPLE 59 (+)-1-(Benzothiazol-2-yl)-4-](1,4-Benzodioxan-2-yl)Methylaminomethyl]Piperidine Stage A:(+)-2-Hydroxymethyl-1,4-Benzodioxane

The expected product is obtained from catechol and S-(+)-glycidyltosylate by following the technique described by A. DELGADO et al.(Tetrahedron Letters, 1988, 3671-4).

Melting point: 70° C.

Stage B: (+)-2-Tosylmethyl-1,4Benzodioxane

After dissolving the compound obtained at stage A in pyridine and addingan equivalent amount of tosyl chloride, the mixture is stirred for 48hours at room temperature. The expected product is obtained afterwashing with diluted hydrochloric acid then with sodium bicarbonate andfinally with water.

Melting point: 60° C.

Stage C: (+)-1-Benzothiazol-2yl)-4-[(1,4-Benzodioxan-2yl)Methylaminomethyl]Piperidine

The expected product is obtained by proceeding as at stage B of Example5, but replacing the 2-mesyloxymethyl-1,4-benzodioxane by the productobtained in the preceding stage.

Melting point: 132° C.

Optical rotation: αD²⁰° C.=+ 89.8° (C=10 mg/ml/CHCl₃)

    ______________________________________                                        Elemental microanalysis:                                                                 C %  H %        N %    S %                                         ______________________________________                                        Calculated:  66.81  6.37       10.62                                                                              8.11                                      Found:       66.44  6.49       10.78                                                                              8.25                                      ______________________________________                                    

EXAMPLE 60 (-)-1-(Benzothiazol-2-yl)-4-[(1,4-Benzodioxan-2-yl)Methylaminomethyl]Piperidine

The expected product is obtained by proceeding as in Example 59 butreplacing at stage A (S)-(+)-glycidyl tosylate by (R)-(-)-glycidyltosylate.

Melting point: 131° C.

Optical rotation: ₆₀ D²⁰° C.=-- 89.9° (C=10 mg/ml/CHCl₃).

    ______________________________________                                        Elemental microanalysis:                                                                 C %  H %        N %    S %                                         ______________________________________                                        Calculated:  66.81  6.37       10.62                                                                              8.11                                      Found:       66.57  6.30       10.70                                                                              8.20                                      ______________________________________                                    

PHARMACOLOGICAL STUDIES OF THE DERIVATIVES OF THE INVENTION EXAMPLE 61Test of Affinity for 5-HT_(1A) Receptors in Vitro

The affinity of the compounds of the invention for 5-HT_(1A) receptorswas measured relative to that of 8-hydroxy-2-(dipropylamino)tetraline(8-OH-DPAT) which has a very great affinity for the 5-HT_(1A) sitescombined with a great selectivity.

The tests were carried out on tissue from the hippocampus of decapitatedmale Wistar rats. The rats were sacrificed 48 hours before theexperiment and the isolated tissues were preserved at -86° C.

In order to prepare the membranes, the tissues were homogenized at 0° C.in 20 volumes of 50 mM Tris HCl buffer solution (pH 7.7, adjusted with 5N HCl at 25° C.), with a Polytron homogenizer for 6 seconds. The wholewas then centrifuged (35,000 g for 20 minutes at 4° C.). Homogenizationfollowed by centrifugation was repeated a second time under the sameconditions. The pellet thus obtained was suspended for a final time in20 volumes of the above buffer, incubated for 15 minutes at 37° C., thenagain centrifuged. The final pellet was then suspended in 100 volumes ofthe incubation buffer (Tris 50 mM, pargyline 10 μM, CaCl₂ 4 mM, ascorbicacid 0.1% (w/v), pH adjusted to 7.7 with 5 N HCl at 25° C.).

The compounds to be tested were put into solution in the incubationbuffer. Test solutions were prepared by placing in 12×75 mm glass tubes,10 μl of the solution of the compounds to be tested, 100 μl of asolution containing 0.4 mM of [³ H]-8-OH-DPAT (specific radioactivity205 Ci/mmol). Non-specific binding was determined with the aid of asolution of 5-hydroxytryptamine (10 μM), and represented 5 to 10% of thefinal binding. The tubes were incubated for 30 minutes at 37° C. Thesolutions were then filtered through glass fiber filters pretreated with0.1% of polyethyleneimine. The filters were then rinsed twice with 5 mlof the incubation buffer at 4° C., then placed in scintillation vials towhich was added "Picofluor" scintillation liquid. Radioactivity was thendetermined with the aid of external standards.

The pKi values were determined by the CheungPrusoff equation: ##EQU1##

The compounds of the invention had a great affinity for the 5-HT sites.The compound of Example 16 had a pKi equal to 9.3; that of Example 44was equal to 9.0.

EXAMPLE 62 In Vivo Test of "Tail-Flicks"

The potential of the compounds of the invention to act in vivo on the5-HT_(1A) receptors was brought out following a method perfected byMillan et al. (Neurosci. Lett., 1989, 107, 227-232). Subcutaneousinjection of 8-OH-DPAT induces in the rat, under vacuum, markedspontaneous movements of the tail. This model then was used to evaluatethe potential of the compounds of the invention administered bysubcutaneous injection, to interact with the 5-HT_(1A) receptors in therat. The ED₅₀, that is the amount which reduces the action of 8-OH-DPATby 50%, was thus determined.

This was equal for example, to 0.31 mg/kg for the compounds of Examples16 and 44, which implies that, in this test, these compounds haveantagonist properties towards the 5-HT_(1A) receptors.

EXAMPLE 63 Pharmaceutical Composition

Tablet: formulation for 1000 tablets giving 2 mg of active principle.

    ______________________________________                                        1-(Benzothiazol-2-yl)-4-[(8-methoxy-                                                                     2 g                                                1,4-benzodioxan-2-yl)methylaminomethyl]-                                      piperidine dihydrochloride                                                    Hydroxypropylcellulose     2 g                                                Wheat starch               10 g                                               Lactose                    100 g                                              Magnesium stearate         3 g                                                Talc                       3 g                                                ______________________________________                                    

We claim:
 1. A compound selected from those of formula (I) : ##STR20##in which: X represents sulfur,R represents hydrogen or A: ##STR21## inwhich: Z represents oxygen or CH₂, Y represents hydrogen, Y' representshydrogen, or, Y and Y' form together oxygen, R₁ represents hydrogen,halogen, linear or branched lower alkyl, or linear or branched loweralkoxy, R'₁ represents hydrogen, halogen, or linear or branched loweralkoxy, R₂ represents hydrogen or linear or branched lower alkyl, and mis equal to 0 or 1, R' represents hydrogen, linear or branched loweralkyl or A, E or F, with the qualification that R' represents hydrogenwhen R represents the group G, the term lower indicates that the groupsthus qualified have 1 to 6 carbon atoms, as well as its enantiomers,diasteroisomers, and epimers an additional salts thereof with apharmaceutically, acceptable, acid.
 2. A compound as claimed in claim 1,wherein X represents a sulfur atom.
 3. A compound as claimed in claim 1,wherein R represents an optionally substituted (1,4-benzodioxan-2-yl)methyl group.
 4. The compound as claimed in claim 1, which is1-(benzothiazol-2-yl)-4-[(8-methoxy-1,4-benzodioxan-2-yl)methylaminomethyl]piperidine, its enantiomers and diastereoisomers aswell as its addition salts with a pharmaceutically acceptable acid.
 5. Amethod for treating a living animal or human, afflicted with pain,comprising the step of administering to the said living animal or humanan amount of a compound of claim 1 which is effective for alleviation ofsaid condition.
 6. A pharmaceutical composition useful in the treatmentof pain, containing as active principle an effective amount of acompound as claimed in claim 1, in combination with apharmaceutically-acceptable excipient or vehicle.